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About Type 2 Asthma

Asthma has no single cause. Genetic predisposition is clear from the literature, however gene-by-environment interaction is likely responsible for the global variation in the prevalence for asthma.

Type 2 asthma is thought to develop as a result of inhaled antigens, allergic sensitisation and an inflammatory response caused by deviation of the Th2 immune system, infiltration of activated mast cells, eosinophils, neutrophils and basophils.1,2 It is often associated with an earlier age of onset than non-Type 2 asthma.3

Patients also have a higher prevalence of Type 2 inflammatory diseases, such as atopic dermatitis, while non-Type 2 asthma is typically associated with external (extrinsic) factors such as obesity, smoking and gender.4

A complex interplay

The notion of differentiation between Type 2 and non-Type 2 molecular phenotypes has been contested.

This is borne out by a study conducted by Seys S, et al (2017)5 which identified 5 unique asthma molecular phenotypes by biological clustering and found that Type 2 cytokines clustered with non-Type 2 cytokines in 4 out of 5 clusters. Their research points towards significant heterogeneity among asthmatic patients with Type 2 inflammation.

Defining Type 2 asthma, therefore, is a subject of intense investigation as it encompasses a wide range of endotypes and subendotypes.1,6 Consequently, the global prevalence of Type 2 versus non-Type 2 asthma is an area of ongoing research.

Prevalence of Type 2 Asthma

Over the past 20 years, studies have shown discrepancies around the exact prevalence of asthma in patients worldwide, ranging from 7% in France and Germany, 11% in the US and 15–18% in the UK.7 Due to the difficulty in predicting prevalence rates, there is also contention within Type 2 and non-Type 2 cluster phenotypes.

Type 2 asthma is further characterised by varying levels of ‘Th2 driven inflammation’ — ‘Th2-high’ and ‘Th2-low’ endotypes – with the former being diagnosed in roughly 50% of the mildly asthmatic population.1

However, while the prevalence of both Th2-high and Th2-low asthma has historically been considered to be the most commonly observed form within the asthma patient population, this notion has been challenged in more recent literature.

Type 2 asthma is a complex heterogeneous disease that encompasses a range of phenotypes and biomarkers8,9

As research is uncovering the heterogeneity within each class of asthma, more is being understood about this complex disease, with focus on how the cytokine milieu in the lung plays a critical role in the development and pathogenicity of Type 2 asthma, and how it contributes to disease severity.

TYPE 2 ASTHMA10

Mild corticosteroid-naïve or corticosteroid-responsive
early-onset asthma

Moderate-to-severe early-onset corticosteroid-treated atopic asthma

Late-onset eosinophilic asthma

Mixed immune response, including:

  • Type 2 factors + very severe characteristics
  • Autoimmunity
  • Neutrophils
  • Type 1 factors

    Adapted from Ray A, et al 2015.10

THE EMERGING
CONCEPT
OF TYPE 2
INFLAMMATION

Type 2 inflammation characterises a type of asthma that involves Type 2 innate immune cells, such as ILC2 and adaptive immune cells such as Th2 cells.1

Type 2 asthma is believed to encompass a range of eosinophilic and allergic asthma phenotypes, as well as a range of asthma biomarkers, including eosinophils or immunoglobulins such as IgE.

The cytokines IL-4, IL-5, and IL-13 are believed to be some of the key drivers of inflammation in Type 2 asthma from both the innate and adaptive immune systems1 and can be indicators of disease severity.4 Other cells such as ILC2, mast cells and eosinophils, also produce these cytokines, starting a cascade response.1,4

 
THE
ROLE OF
BIOMARKERS

The term asthma has historically encompassed a broad array of patient characteristics, or phenotypes, from mild allergic asthma to severe persistent asthma. However, more recently, studies have shown that severe persistent asthma is not a stand-alone phenotype but has its own heterogeneity of pathophysiology and clinical presentation representative of this group of difficult-to-treat patients.9

While this heterogeneity has proved problematic in regard to identifying the pathophysiology of severe asthma, the complex array of secreted immunoglobulins, cytokines, chemokines and inflammatory cells has made subtyping asthma an attractive approach for identification of biomarkers to guide therapy options.8,9

For example, patients with low serum IgE are more likely to have received a diagnosis of non-Type 2 asthma, linked to smoking and obesity. Conversely, serum levels of the protein periostin, variable serum IgE levels, high FeNO and the presence of eosinophils, have shown potential as biomarkers for certain subsets of Type 2 asthma.9,10,13–15

Allergic Asthma is Mediated by the Type 2 Immune Response13

IL-4 drives Th2 cell differentiation13

IL-4 and IL-13 promote class switching of B cells to produce IgE13

IL-5 mediates the differentiation of eosinophils in bone marrow and development and function of mast cells and basophils13

Adapted from Robinson D, et al 2017.13

IL-4, IL-5 and IL-13 play an important role in allergic inflammation in asthma1

BURDEN OF
ASTHMA

Learn about the prevalence and
healthcare burden of asthma.

Explore facts & figures

DEFINING
ASTHMA CONTROL

Discover how asthma control goes
beyond exacerbation reduction.

Get more information

TYPE 2
COMORBIDITIES

Type 2 inflammation has been associated with several chronic conditions. Find out how they can present additional challenges.

Learn about comorbidities

EOS, eosinophils; FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; ILC2, Type 2 innate lymphoid cells; Th2, T helper cell type 2; UK, United Kingdom; US, United States.

References:
  1. Becerra-Diaz M, Wills-Karp M and Heller N. New perspectives on the regulation of type II inflammation in asthma. F1000Res. 2017;6:1014.
  2. Holgate S, et al. Asthma. Nat Rev Dis Primers. 2015;1:15025.
  3. Ilmarinen P, Tuomisto L and Kankaanranta H. Phenotypes, Risk Factors, and Mechanisms of Adult-Onset Asthma. Mediators Inflamm. 2015;514868.
  4. Lambrecht B and Hammad H. The immunology of asthma. Nat Immunol. 2015;16(1):45–56.
  5. Seys S, et al. Cluster analysis of sputum cytokine-high profiles reveals diversity in T(h)2-high asthma patients. Respir Res. 2017;18(1):39.
  6. Agache I and Akdis C. Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine. Allergol Int. 2016;65(3):243–252.
  7. Peters S, et al. Uncontrolled asthma: a review of the prevalence, disease burden and options for treatment. Respir Med. 2006;100(7):1139–51.
  8. Wenzel S. Emergence of biomolecular pathways to define novel asthma phenotypes: type-2 immunity and beyond. Am J Respir Cell Mol Biol. 2016;55(1):1–4.
  9. Ray A, et al. Current concepts of severe asthma. J Clin Invest. 2016;126(7):2394–2403.
  10. Ray A, Oriss T and Wenzel S. Emerging molecular phenotypes of asthma. Am J Physiol Lung Cell Mol Physiol. 2015;308(2):130–140.
  11. Peters M, et al. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133(2):388–389.
  12. Woodruff P, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(5):388–95.
  13. Robinson D, et al. Revisiting Type 2-high and Type 2-low airway inflammation in asthma: current knowledge and therapeutic implications. Clin Exp Allergy. 2017;47(2):161–175
  14. Bjermer L, et al. Current evidence and future research needs for FeNO measurement in respiratory diseases. Respir Med. 2014;108(6):830–841.
  15. Brightling C, et al. Comparison of airway immunopathology of eosinophilic bronchitis and asthma. Thorax. 2003;58(6):528–32.
  16. Korevaar D, et al. Diagnostic accuracy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and meta-analysis. Lancet Respir Med. 2015;3(4):290–300.